-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3638 Serious Adverse Drug Reactions (sADRs) Involving Hematology and Resulting in Black Box Warnings or FDA Non-Approval: Results from the First Quarter Century of RADAR/Sonar

Program: Oral and Poster Abstracts
Session: 901. Health Services and Quality Improvement: Non-Malignant Conditions Excluding Hemoglobinopathies: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality)
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Swetha Kambhampati Thiruvengadam, MD1, Nikhil Thiruvengadam2*, Steven T. Rosen, MD3, Chadi Nabhan, MD, MBA4, Kevin Knopf, MD MBA5*, Linda Martin, PhD6*, Kenneth R. Carson, MD, PhD7, Peter Georgantopoulos8*, Gretchen Watson6*, Edward Smith9*, Edward Zyszkowski10*, Sony Jacob11*, Dennis Banegas, BA12*, William Hrushesky, MD6*, Iain Cumming Macdougall, BSc, MBBChir, MD, MRCP, FRCP13*, Manuel Gonzalez-Brio14*, David Aboulafia, MD15*, Oliver Sartor16*, Robert Peter Gale17* and Charles Bennett, MD11

1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
2Gastroenterology, Loma Linda University, Loma Linda, CA
3Department of Hematology and HCT, City of Hope Comprehensive Cancer Center, Duarte, CA
4University of South Carolina, Deerfield, IL
5U of SOuth Carolina, COLUMBIA, SC
6U of South Carolina, Columbia
7Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago
8U of South Carolina, Columbia, SC
9University of South Carolina, Columbia, CA
10University of South Carolina, Columbia
11University of South Carolina, Columbia, SC
12Smart State Center for Medication Safety and Efficacy, University of South Carolina, COLUMBIA, SC
13King's College Hospital, London, GBR
14University of Miami, Miami, FL
15Virginia Mason Clinic, Seattle
16Mayo Clinic, Rochester, MN
17Centre For Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, GBR

Background: Two National Cancer Institute-funded pharmacovigilance programs have identified 49 serious hematology-related ADRs since 1998. The programs, called RADAR (Research on Adverse Drug events and Reports) and then SONAR (Southern Network on Adverse Reactions) involve > 50 institutions and > 75 co-investigators worldwide. The work builds on three prior studies evaluating “Davids and Goliaths” in medical oncology and in cardiology (PLOS One, eClinicalMedicine, and Journal of Scientific and Professional Integrity). Here we review the hematology focused safety investigations of RADAR/SONAR.

Methods: Data were based on initial safety signals being identified by a RADAR/SONAR co-investigator. Then, case-series were derived. Collaborations with basic scientists allowed for basic science correlative studies. Results were disseminated primarily as Brief Report in the literature and Black Box warnings on the related drug. In some instances, studies identified hematologic toxicities that prevent FDA from approving a submitted drug application.

Results: sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient). Meta-analyses provided data for epoetin- and darbepoetin-associated mortality among cancer patients and lenalidomide- and thalidomide-associated venous thromboembolism. Following the onset of the COVID-19 pandemic, RADAR/SONAR investigated social media and pre-prints (COVID-19 vaccine associated cerebral vein thrombosis and immune thrombocytopenia). Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity). Basic science correlative studies identified ADAMTS13 autoantibodies (ticlopidine), leachates that developed in a multi-dose vial (peginesatide), anti-red blood cell antibodies (epoetin-associated pure red cell aplasia), and high-risk genes (fluoroquinolones and rituximab). Overall, RADAR/SONAR studies are estimated to have saved over 1 million lives and also resulted in overall payments to the Department of Justice of $1.5 billion (related to marketing of unsafe drugs).

Discussion: RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused investigations such as the CERSI network and the SENTINEL network (both are NIH funded) should be broadened to include a hematology-focused safety center.

Disclosures: Thiruvengadam: Genentech: Research Funding; ADC-Therapeutics: Research Funding; Ipsen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy, Research Funding; Abbvie: Consultancy. Rosen: Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH